Tuberculin Skin Test Conversion among Individuals with Human Immunodeficiency Virus Infection on Antiretroviral Therapy in a Referral Teaching Hospital, Tehran, Iran.

Background
The risk of tuberculosis (TB) is greater for individuals with human immunodeficiency virus (HIV) who are on combined antiretroviral therapy (c-ART) than for the normal population. Therefore, the detection and treatment of latent tuberculosis infections is recommended for all HIV-positive persons with positive tuberculin skin tests (TSTs).


Materials and Methods
This retrospective cohort study included all HIV-positive individuals with CD4 lymphocyte counts greater than 200 cells/μL and negative TST results, who were taking antiretroviral drugs and had been referred to Imam Khomeini Teaching Hospital Consultation Centre for Clients with Risky Behaviors in Tehran, Iran, from 2008 to 2013. TST conversion to positivity is defined as an induration increase of at least 5 mm compared with a previously negative TST result within a 1-year period. Conversion rates are expressed in person-years of observation.


Results
A total of 113 patients were included in our study. At 1 year, 9 of the 113 TST-negative patients taking c-ART became TST-positive (8%; 8 males and 1 female). The TST conversion incidence rate was 10.09/100 person-years. TST conversion was only found to be associated with sex (odds ratio: 8.64; 95% confidence interval: 1.04-7.56, p = 0.032).


Conclusion
Our results suggest that TSTs should be administered to all HIV-positive patients before beginning isoniazid preventive therapy in Iran.

. In a regional study, 7.2% of HIV-infected persons in Iran were co-infected with TB (3). According to a 2010 statement from the Iranian Ministry of Health and Medical Education, a total of 10,485 TB infections were reported in Iran, with 230 (2.2%) of the individuals also being HIV-positive (4). Accordingly, the early diagnosis of latent TB and the prevention of active TB by isoniazid are critical for HIV-infected individuals (5). Isoniazid preventive therapy (IPT) for 6-9 months reduces the risk of TB reactivation among HIV-infected persons by 40-70% (6).
The lifetime risk of TB reactivation is 20% among HIVinfected people, which is defined by a 10-mm or greater TANAFFOS induration in a tuberculin skin test (TST). A TST reaction, using purified protein derivative (PPD) in the Mantoux technique, is useful method for latent tuberculosis infection (LTBI) screening (7). However, this test is reported to be less sensitive among HIV-positive patients with low CD4 positive lymphocyte counts (8).
This study aimed to evaluate the TST reaction and its yearly conversion in HIV-infected persons who had CD4 counts ≥200 cells/µL and were TST-negative at the beginning of combined anti-retroviral therapy (c-ART) in a Consultation Centre for Clients with Risky Behaviors in Imam Khomeini Teaching Hospital.   (10). A meta-analysis found that IPT reduced the risk of active TB by 64% among adults with positive TSTs (11). However, trials evaluating the long-term effects of IPT on PPD conversion rates in HIV infection are needed. We did not have data on other risk factors for LTBI, such as close contact with patients with active TB and a history of incarceration. The lack of this information is a weak point of our study.

MATERIALS AND METHODS
Our study found no association between chest radiograph abnormalities and PPD conversion rates (odds ratio: 0.77, 95% confidence interval: 0.08-7.05, p = 0.59), which is in line with a study from Uganda (6). In another study, the majority of participants with positive TST results had a negative chest radiograph; these authors concluded that chest radiography does not demonstrate the benefit of IPT for clinicians (12). To the best of our knowledge, no studies have shown that an abnormal chest x-ray is a risk factor for PPD conversion.
In contrast to a previous study (6), we found that the rate of PPD conversion was significantly higher for males (Table 2). Female sex was independently associated with negative TSTs among HIV-infected adults in Thailand (13).
Another study reported that 66-75% of patients with TB in 12 Asian countries were male; therefore, men may account for approximately two-thirds to three-quarters of the burden of TB disease in Asia (14). In China, Gao et al.
found that LTBI rates were higher in men than in women (p < 0.0001) (15). These reports indicate that men may be more susceptible to TB than women. It remains unclear if male sex is a risk factor for TB. In addition to behavioral factors (e.g., smoking, alcohol, and drug use), biological components also should be considered (16). One study indicated that estradiol acts as an immunity-enhancing mediator in women, with testosterone acting as a mediator inhibiting the immune response (17).
In line with a previous study (18), the women in our study had higher mean CD4 cell counts than men after 1 year of antiretroviral therapy (p < 0.001). More frequent side effects were also reported for all classes of antiretrovirals in women (19). Other studies concluded that virologic suppression was achieved more rapidly in women and the response was more durable; therefore, women may experience more benefits for outcomes than men (20,21).
Oni et al. reported an 8.5% prevalence rate for asymptomatic TB disease among HIV-infected persons.
The authors showed that 61% of patients with subclinical TB had a CD4 count of >200 cells/µL; however, a low CD4 count appeared to be predictive of subclinical TB (22). The TST conversion in some of our patients could be due to subclinical active TB. All of our participants were screened for TB symptoms (cough, fever, weight loss, and night sweats). However, we did not collect sputum samples for microscopy and culture, which is a weak point of our study.
Some studies reported that IPT caused a greater reduction in the risk of active TB for TST-positive HIVinfected adults than in TST-negative adults (11,23). In our study, we found a low incidence of TST conversion.
Therefore, we recommend that TSTs be performed for all HIV-positive patients before initiating IPT because the increase in CD4 following c-ART may affect TST results. In